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    Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/73987

    Title: Synthesis and Biology of Isomalyngamide A Analogs Containing Ribose as Anti-Migration and Anti-Tube Formation Inhibitors
    Authors: 石晴瑩;Shih, Ching-Ying
    Contributors: 化學學系
    Keywords: Isomalyngamide A;Anti-tube formation;Anti-migration;Isomalyngamide A;Anti-tube formation;Anti-migration
    Date: 2017-07-24
    Issue Date: 2017-10-27 12:57:39 (UTC+8)
    Publisher: 國立中央大學
    Abstract: 三陰性乳癌是一種類型的乳癌,其具有高復發性、高死亡率、高轉移性,轉移是造成病患主要的死亡原因,因為其轉移不同於其他癌症,三陰性乳癌的腫瘤還沒長到一定大小就具有轉移性,且對於腦及肺的轉移率比其他類型的乳癌都還要高。由於缺少了其他乳癌細胞常見的受體,所以目前也沒有針對三陰性乳癌的標靶藥物,以往治療三陰性乳癌的方式僅限於手術及化療,現在,搭配抗轉移、抗血管增生藥物來延長病患的存活時間已經是一種治療趨勢。
    幾年前,我們實驗室發現藍綠藻分離出的天然物 isomalyngamide A、A-1 對三陰性乳癌的細胞株 MDA-MB-231 具有很強的抗轉移效果,但是這種天然物的合成很困難,因此,我們實驗室設計了一些骨架簡單、易於合成的類似物,並且利用醣基化來增加它的抗轉移能力。在這篇論文中,我們將會以核糖、不同的長度的 linkers 合成一系列化合
    在這系列醣基化的 isomalyngamide A 衍生物中,化合物 CY01 具有最好的MDA-MB-231 細胞抗轉移活性,其 IC50 值為 7.56μM;除此之外,我們實驗室也發現 CY01對 HUVEC (人類臍帶靜脈內皮細胞) 的 tube formation 有不錯的抑制效果,而 Western blot 測試揭露CY01 是透過抑制 pVEGFR2/pAKT 的信號路徑來達到抗轉移與抗 tube
    formation 的效果。;Triple-negative breast cancer is a subtype of breast cancer that demonstrates unique properties of high recurrence, mortality, and metastasis. Metastases to a person’s lung and brain are the two leading causes of death by triple-negative breast cancer. Since triple-negative breast cancer tumors lack common receptors that other types of breast cancer have, there is no specific target drugs against triple-negative breast cancer in clinic. Traditional treatments for triple-negative breast cancer patients are surgery and chemotherapy; yet in nowadays, treatments combined with anti-migration and anti-angiogenesis drugs are the latest trend of therapy.
    Previously our laboratory identified and isolated isomalyngamide A and A-1 from marine cyanobacteria. We discovered that these two substances had profound anti-migration effects against triple-negative breast cancer cell line MDA-MB-231. However, routine preparation/production of isomalyngamides required tedious separations of intermediates and lengthy total synthesis. Hence, our laboratory designed a series of analogs of isomalyngamide A with the aid of simple and optimized synthetic procedures. Accordingly we uncovered that compounds derived from glycosylation of isomalyngamide A analogs have better anti-metastatic properties than nonglycosylated ones. Based on these results, we investigated the structure-activity relationship of those synthetic glycosylated isomalyngamide A analogs where the ribose and different lengths of linkers were incorporated in this study.
    Among this series of glycosylated isomalyngamide A analogs (CY01-CY12), CY01 is the best compound showing the potential against MDA-MB-231 under nontoxic concentration level. Furthermore, we uncovered that CY01 suppressed tube formation of HUVEC (human umbilical vein endothelial cells) efficiently. Western blot assay revealed that CY01 inhibited metastasis and tube formation by inhibiting the pVEGFR2/pAKT signaling pathway.
    Appears in Collections:[化學研究所] 博碩士論文

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